Renin is a proteolytic enzyme, belonging to the class of the hydrolases secreted by the juxtaglomerular apparatus cells in the kidneys, which, if activated, passes to blood, where it induces the hydrolysis of angiotensin and the following release of the decapeptide angiotensin I, which is hydrolyzed in the lungs, in the kidneys and in many other organs to provide the octapeptide angiotensin II.
This peptide increases blood pressure both directly, inducing arterial vasoconstriction, and indirectly, causing the release from adrenergic glands of the aldosterone, a hormone which raises the retention of sodium ions, inducing an increase of the extracellular fluid volumes.
Renin inhibitors reduce the formation of angiotensin I and consequently of angiotensin II. The reduced concentration of these peptides is the main reason for the hypotensive effect of these inhibitors, making them useful in the prevention and the treatment of hypertension, of heart failure, glaucoma, myocardial infarction and renal failure.
Aliskiren is the first of a new class of orally available potent renin inhibitors approved by FDA and EMEA.
In particular, its hemifumarate salt is registered by Novartis with the commercial name of Tekturna®. Chemically it is defined as (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide hemifumarate. Aliskiren (1) is schematized in the picture below:

European patent EP 0678503 B1 claims Aliskiren (specifically its hemifumarate salt) and the method to produce it. This process involves the opening of the lactone ring in compound (I) by treatment with an amine (4) in presence of triethylamine (TEA) and 2-hydroxypyridine, as represented in the scheme below:

Similar processes are described in international patent applications WO 02/08172 A1 and WO 02/02508 A1, assigned to Speedel Pharma, in patent application US 2010/0124550 A1 assigned to Auspex Pharmaceuticals, or in international patent application WO 2010/024772 A1 assigned to Medivir Ab.
Lactone ring opening can be achieved by treatment with the amine (4) using a solvent and a base such as triethylamine or dimethylaminopyridine, as described in international application WO 2007/039183 A1 assigned to Novartis.
An alternative process is described in “A stereocontrolled synthesis of 2R-benzyl-5S-tert-butoxycarbonylamino-4R-(tert-butyldimethylsilanyloxy)-6-phenyl-hexanoic acid”; A. Nadin et al.: Tetrahedron (2001), 57(9), 1861-1864, where the lactone ring is hydrolyzed to the corresponding hydroxy acid, followed by protection of the alcohol and formation of the amide bond using a coupling agent.
A direct aminolysis process is described in “Formal Total Synthesis of the Potent Renin Inhibitor Aliskiren: Application of a SmI2-Promoted Acyl-like Radical Coupling” K. B. Lindsay et al.: Journal of Organic Chemistry (2006), 71(13), 4766-4767. According to the process described therein, the lactone ring in compound (I) is treated with the amine (4) in presence of Al(CH3)3.
Another synthetic method to open a lactone ring, described in international application WO 03/103653 A1 assigned to Elan Pharmaceuticals, entails the reaction with the amine (4) in the presence of a carboxylic acid, specifically acetic acid.
However, all the process cited above provide the desired amide with extremely low yields and in some cases involve the use of reagents not easily handled on industrial scale.
Improved processes of direct aminolysis are described in “A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate”, H. Rüeger et al.: Tetrahedron Letters (2000), 40(51), 10085-10089, in which compound (I) is reacted under solvent free conditions with the amine (4), triethylamine and 2-hydroxypyridine; or in European patent EP 1789377 B1, where the same reaction is conducted using a solvent, particularly methyl-tert-butylether. These two processes provide the desired amide in extremely low yields.
A further improvement in the synthetic process of lactone ring opening is reported in “Amide Bond Formation via Reversible, Carboxylic Acid-Promoted Lactone Aminolysis”, M. A. Foley et al.: Organic Process Research & Development (2010), 14(5), 1177-1181, or in international patent application WO 2011/019789 A1 (assigned to Novartis), where the best yields for the aminolysis reaction are obtained treating the lactone (I) with an excess of amine (4) under solvent free conditions and in the presence of 2-ethylhexanoic acid as catalyst.
These two synthetic processes, which are indeed improvements with respect to the prior art, are affected by very low yields which could be enhanced to acceptable levels (HPLC measured conversion of 90%) only using enormous excesses of the amine (4) (up to 100 equivalents).
Furthermore the use of solvent free conditions can be problematic on an industrial scale.
It is thus an object of the present invention to provide an industrial process for the production of active ingredients and the intermediates thereof, particularly Aliskiren, which entails an opening of lactone or lactam ring as a key step, leading to an improved yield compared to the processes of the prior art.